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Study of the Anti-PD-1 Antibody Nivolumab in Combination With Dabrafenib and/or Trametinib

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ClinicalTrials.gov Identifier: NCT02357732
Recruitment Status : Withdrawn (PI decided not to proceed)
First Posted : February 6, 2015
Last Update Posted : December 11, 2015
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Hussein Tawbi, University of Pittsburgh

Brief Summary:
This study evaluates nivolumab in combination drug treatments involving 1) nivolumab and dabrafenib 2) nivolumab and trametinib and 3) nivolumab, dabrafenib and trametinib in patients with BRAF or NRAS-mutated metastatic melanoma.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: Nivolumab Drug: Trametinib Drug: Dabrafenib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of the Anti-PD-1 Antibody Nivolumab in Combination With Dabrafenib and/or Trametinib in Patients With BRAF or NRAS-mutated Metastatic Melanoma
Study Start Date : August 2015
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Nivolumab and Dabrafenib Combination (doublets)
Level -1, Nivolumab 1mg/kg IV every 2 weeks (q2 weeks); Dabrafenib 100mg by mouth (PO) twice a day(BID) every day (QD); Level 1, Nivolumab 1mg/kg IV q2 weeks; Dabrafenib 150mg PO BID QD; Level 2, Nivolumab 3mg/kg IV q2 weeks; Dabrafenib 150mg PO BID QD;
Drug: Nivolumab
Drug: Dabrafenib
Experimental: Nivolumab and Trametinib Combination (doublets)
Level -1, Nivolumab 1mg/kg IV q2 weeks; Trametinib 1mg PO QD; Level 1, Nivolumab 1mg/kg IV q2 weeks; Trametinib 2mg PO QD; Level 2, Nivolumab 3mg/kg IV q2 weeks; Trametinib 2mg PO QD;
Drug: Nivolumab
Drug: Trametinib
Experimental: Nivolumab, Dabrafenib and Trametinib Combination (triplet)
Level -1, Nivolumab 1mg/kg IV q2 weeks; Dabrafenib 150mg PO BID; Trametinib 1mg PO QD; Level 1, Nivolumab 1mg/kg IV q2 weeks; Dabrafenib 150mg PO BID; Trametinib 2mg PO QD; Level 2, Nivolumab 3mg/kg IV q2 weeks; Dabrafenib 150mg PO BID; Trametinib 2mg PO QD;
Drug: Nivolumab
Drug: Trametinib
Drug: Dabrafenib



Primary Outcome Measures :
  1. To determine the Maximally Tolerated Dose and/or Recommended Phase II Dose (RP2D) of nivolumab in combination with dabrafenib and/or trametinib in patients with BRAF- or NRAS-mutated metastatic melanoma [ Time Frame: The first four weeks of dosing ]
    It is planned to determine the maximum tolerable dose with a modified version of the standard "up and down" (3+3) dose-finding method using cohorts of 3 patients. At the start of the trial, three patients will be placed on dose level 1. The decision rules based on the observed dose limiting toxicities (DLTs) in this and subsequent cohorts are given. Only DLTs observed in a patient during the first cycle (28 days) will be used for the dose escalation decisions. Patients will be considered evaluable for toxicity if they receive 1 complete cycle of therapy, or if they experience DLT; in-evaluable patients will be replaced.


Secondary Outcome Measures :
  1. Antitumor Effects and Immune Related Response [ Time Frame: Every twelve weeks for three years while on study drug ]
    Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and by the Immune Related Response Criteria. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III melanoma with BRAF V600E/K or NRAS mutations.
  • Prior therapies for metastatic melanoma are allowed, including chemo-, cytokine-, immuno-, biological- and vaccine-therapy as long as they did not include BRAFi, MEKi, or nivolumab. Prior ipilimumab therapy will be allowed with a washout period of 8 weeks and if all autoimmune adverse events have resolved to grade 1.
  • Evidence of evaluable disease.
  • ECOG Performance Status of 0 or 1.
  • Stable CNS disease is allowed. Subjects with brain metastases are eligible if (a) metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; or (b) if they are untreated but asymptomatic and do not require steroid therapy. Patients are excluded if they require high doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration, as this could result in immunosuppression.
  • Patients must have normal organ and marrow function as defined by the normal laboratory ranges. Screening laboratory values must meet the following criteria and should be obtained within 28 days prior to registration:

    • WBC ≥ 2000/μL
    • Neutrophils ≥ 1500/μL
    • Platelets ≥ 100 x103/μL
    • Hemoglobin > 9.0 g/dL
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

  • AST/ALT ≤ 3 x ULN
  • Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

    • Men and women age≥18 years.
    • Life expectancy of greater than12 weeks.
    • Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year.
    • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of nivolumab.
    • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception.
    • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Histologically confirmed metastatic melanoma (Stage IV) with NRAS and BRAF-wild type.
  • Grade 3/4 immune-related AEs on ipilimumab and required more than 12 weeks of immune suppression with corticosteroids.
  • History of interstitial lung disease or pneumonitis.
  • History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Active leptomeningeal metastases or untreated symptomatic brain metastases.
  • Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
  • Require systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Known history of a positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib and trametinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • History of allergy or adverse drug reaction to the study drug components (nivolumab, dabrafenib, or trametinib) or drugs of similar chemical or biologic composition. Patients with a history of severe hypersensitivity reaction to any monoclonal antibody should also be excluded.
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and/or breastfeeding women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dabrafenib and trametinib, breastfeeding should be discontinued if the mother is treated with dabrafenib and trametinib. These potential risks may also apply to other agents used in this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02357732


Sponsors and Collaborators
University of Pittsburgh
Bristol-Myers Squibb
Investigators
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Principal Investigator: Hussein Tawbi, MD University of Pittsburgh Medical Center / Hillman Cancer Center
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Responsible Party: Hussein Tawbi, Associate Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02357732    
Other Study ID Numbers: 14-115
First Posted: February 6, 2015    Key Record Dates
Last Update Posted: December 11, 2015
Last Verified: December 2015
Keywords provided by Hussein Tawbi, University of Pittsburgh:
Metastatic Melanoma
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Trametinib
Dabrafenib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors